Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the Twin Hub of the ABCD-USA Consortium is in response to RFA-DA-15-015; the proposal includes the University of Minnesota (hub leader), Virginia Commonwealth University, Washington University, and the University of Colorado to prospectively determine neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 800 twin pairs, ages 9-10 years, from four sites whose researchers are leaders in twin research, SU and abuse, and neuroimaging of cognitive and emotional functioning will be tested, together with 700 singletons, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD-USA Consortium. Participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) effects of substance use patterns on the adolescent brain; 2) effects of substance use on behavioral and health outcomes; 3) bidirectional relationships between psychopathology and substance use patterns; 4) effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) gateway interactions between use of different substances. The Twin Hub proposes to use classic and co-twin control designs to study genetic vs. environmental contributions to adolescent brain/behavioral development and how these contributions predict SU propensity. Using sophisticated growth trajectory modeling techniques, we will also identify the genetic and environmentally- determined consequences of substance use on brain and behavioral development, including the assessment of gene-by-environment interactions. In addition, we will develop biospecimen resources for future studies of genomic, epigenomic, metabolomics and microbiome changes that may influence substance use and its broad health consequences. Specific to this Twin-Hub, we will obtain baseline and follow-up serum, saliva, and in some cases gut microbiota from biological samples. This work enriches the full ABCD-USA Consortium given that disentangling G and E contributions to individual risk for addiction and sensitivity to SU's neurocognitive effects has highly significant public policy and prevention-based implications.